PROJECT(SUMMARY Melanoma is one of the deadliest forms of skin cancer and affects tens of thousands of people each year. Although novel targeted and immune therapies have been approved, they often work transiently with resistance eventually ensuing, or are accompanied by significant toxicities. The transcriptional program organized by melanoma drivers is poorly understood. Here we propose to dissect the melanoma metastasis-supportive transcriptional program organized by the transcription factor Heat Shock Factor 1 (HSF1). Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. Our preliminary data indicate that the ubiquitin ligase FBXW7 interacts with HSF1 through a conserved motif phosphorylated by GSK3? and ERK1. FBXW7 is either mutated or transcriptionally down-regulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. We proposed to investigate the molecular basis for FBXW7 silencing in melanoma (Aim 1), and dissect the role of HSF1 in melanoma initiation and progression and the effects of FBXW7 loss or silencing on HSF1 stability by using novel in vivo models (Aim 2). In addition, we will identify the HSF1-regulated transcriptome and examine the in vivo effects of a subset of HSF1 direct targets (Aim 3). Our studies will elucidate the metastasis-supportive transcriptional program orchestrated by HSF1 and its regulation by a tumor suppressor (FBXW7) frequently mutated or silenced and will provide us with novel therapeutic targets for melanoma.